Combination therapy comprising glucose reabsorption inhibitors and retinoid-x receptor modulators

ABSTRACT

Combination therapy comprising RXR modulators and glucose reabsorption inhibitors useful for the treatment of diabetes and Syndrome X are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from the provisional applicationU.S. S. No. 60/281,479 filed on Apr. 4, 2001, our Docket NumberORT-1410, which application is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates to a novel method and compositions for thetreatment or prophylaxis of diabetes and Syndrome X.

BACKGROUND OF THE INVENTION

[0003] Diabetes is a chronic disorder affecting carbohydrate, fat andprotein metabolism in animals.

[0004] Type I diabetes mellitus, which comprises approximately 10% ofall diabetes cases, was previously referred to as insulin-dependentdiabetes mellitus (“IDDM”) or juvenile-onset diabetes. This disease ischaracterized by a progressive loss of insulin secretory function bybeta cells of the pancreas. This characteristic is also shared bynon-idiopathic, or “secondary”, diabetes having its origins inpancreatic disease. Type I diabetes mellitus is associated with thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

[0005] Type II diabetes mellitus (non-insulin-dependent diabetesmellitus or NIDDM) is a metabolic disorder involving the dysregulationof glucose metabolism and impaired insulin sensitivity. Type II diabetesmellitus usually develops in adulthood and is associated with the body'sinability to utilize or make sufficient insulin. In addition to theinsulin resistance observed in the target tissues, patients sufferingfrom type II diabetes mellitus have a relative insulin deficiency—thatis, patients have lower than predicted insulin levels for a given plasmaglucose concentration. Type II diabetes mellitus is characterized by thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

[0006] Syndrome X, also termed Insulin Resistance Syndrome (IRS),Metabolic Syndrome, or Metabolic Syndrome X, is recognized in some 2% ofdiagnostic coronary catheterizations. Often disabling, it presentssymptoms or risk factors for the development of Type II diabetesmellitus and cardiovascular disease, including impaired glucosetolerance (IGT), impaired fasting glucose (IFG), hyperinsulinemia,insulin resistance, dyslipidemia (e.g., high triglycerides, low HDL),hypertension and obesity.

[0007] Therapy for IDDM patients has consistently focused onadministration of exogenous insulin, which may be derived from varioussources (e.g., human, bovine, porcine insulin). The use of heterologousspecies material gives rise to formation of anti-insulin antibodieswhich have activity-limiting effects and result in progressiverequirements for larger doses in order to achieve desired hypoglycemiceffects.

[0008] Typical treatment of Type II diabetes mellitus focuses onmaintaining the blood glucose level as near to normal as possible withlifestyle modification relating to diet and exercise, and whennecessary, the treatment with anti-diabetic agents, insulin or acombination thereof. NIDDM that cannot be controlled by dietarymanagement is treated with oral antidiabetic agents.

[0009] Although insulin resistance is not always treated in all SyndromeX patients, those who exhibit a prediabetic state (e.g., IGT, IFG),where fasting glucose levels may be higher than normal but not at thediabetes diagnostic criterion, is treated in some countries (e.g.,Germany) with mefformin to prevent diabetes. The anti-diabetic agentsmay be combined with pharmacological agents for the treatment of theconcomitant co-morbidities (e.g., antihypertensives for hypertension,hypolipidemic agents for lipidemia).

[0010] First-line therapies typically include mefformin andsulfonylureas as well as thiazolidinediones. Metformin monotherapy is afirst line choice, particularly for treating type II diabetic patientswho are also obese and/or dyslipidemic. Lack of an appropriate responseto mefformin is often followed by treatment with metformin incombination with sulfonylureas, thiazolidinediones, or insulin.Sulfonylurea monotherapy (including all generations of drugs) is also acommon first line treatment option. Another first line therapy choicemay be thiazolidinediones. Alpha glucosidase inhibitors are also used asfirst and second line therapies. Patients who do not respondappropriately to oral anti-diabetic monotherapy, are given combinationsof the above-mentioned agents. When glycemic control cannot bemaintained with oral antidiabetics alone, insulin therapy is used eitheras a monotherapy, or in combination with oral antidiabetic agents.

[0011] One recent development in treating hyperglycemia is focused onexcretion of excessive glucose directly into urine. Specific inhibitorsof SGLTs have been shown to increase the excretion of glucose in urineand lower blood glucose levels in rodent models of IDDM and NIDDM.However, combination therapy comprising a retinoid-X receptor (RXR)modulator and a glucose reabsorption inhibitor has not been contemplatedin the art.

SUMMARY OF THE INVENTION

[0012] The present invention is directed to methods and compositions forthe treatment or prophylaxis of diabetes, Syndrome X, or associatedsymptoms or complications. More specifically, this invention is directedto a novel method of treating diabetes or Syndrome X, or associatedsymptoms or complications thereof, in a subject afflicted with such acondition, said method comprising administering one or more glucosereabsorption inhibitors and administering one or more RXR modulators forthe treatment of diabetes or Syndrome X, or associated symptoms orcomplications thereof.

[0013] One aspect of the invention features a pharmaceutical compositioncomprising a glucose reabsorption inhibitor, an RXR modulator, and apharmaceutically acceptable carrier. The invention also provides aprocess for formulating a pharmaceutical composition, comprisingformulating together a glucose reabsorption inhibitor, an RXR modulator,and a pharmaceutically acceptable carrier.

[0014] An embodiment of the invention is a method for treating diabetesor Syndrome X, or associated symptoms or complications thereof in asubject, said method comprising administering to said subject a jointlyeffective amount of a glucose reabsorption inhibitor and administeringto said subject a jointly effective amount of an RXR modulator, saidcombined administration providing the desired therapeutic effect.

[0015] Another embodiment of the invention is a method for inhibitingthe onset of diabetes or Syndrome X, or associated symptoms orcomplications thereof in a subject, said method comprising administeringto said subject a jointly effective dose of a glucose reabsorptioninhibitor and administering to said subject a jointly effective amountof an RXR modulator, said combined administration providing the desiredprophylactic effect.

[0016] In the disclosed methods, the diabetes or Syndrome X, orassociated symptoms or complications thereof, is selected from IDDM,NIDDM, IGT, IFG, obesity, nephropathy, neuropathy, retinopathy,atherosclerosis, polycystic ovary syndrome or polycystic ovariansyndrome, hypertension, ischemia, stroke, heart disease, irritable boweldisorder, inflammation, and cataracts.

[0017] Also included in the invention is the use of one or more glucosereabsorption inhibitors in combination with one or more RXR modulatorsfor the preparation of a medicament for treating a condition selectedfrom IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy,retinopathy, atherosclerosis, polycystic ovary syndrome or polycysticovarian syndrome, hypertension, ischemia, stroke, heart disease,irritable bowel disorder, inflammation, and cataracts.

DETAILED DESCRIPTION OF THE INVENTION

[0018] All diabetics, regardless of their genetic and environmentalbackgrounds, have in common an apparent lack of insulin or inadequateinsulin function. Because transfer of glucose from the blood into muscleand fatty tissue is insulin dependent, diabetics lack the ability toutilize glucose adequately, which leads to undesired accumulation ofglucose in the blood (hyperglycemia). Chronic hyperglycemia leads todecrease in insulin secretion and contributes to increased insulinresistance, and as a result, the blood glucose concentration isincreased so that diabetes is self-exacerbated (Diabetologia, 1985,“Hyperglycaemia as an inducer as well as a consequence of impaired islecell function and insulin resistance: implications for the management ofdiabetes”, Vol. 28, p. 119); Diabetes Cares, 1990, Vol. 13, No. 6,“Glucose Toxicity”, pp. 610-630). Therefore, by treating hyperglycemia,the aforementioned self-exacerbating cycle is interrupted so that theprophylaxis or treatment of diabetes is made possible.

[0019] U.S. Pat. No. 6,153,632 to R. Rieveley discloses a method andcomposition stated to be for the treatment of diabetes mellitus (Type I,Impaired Glucose Tolerance [“IGT”] and Type II), which incorporates atherapeutic amount of one or more insulin sensitizers along with one ormore of an orally ingested insulin, an injected insulin, a sulfonylurea,a biguanide or an alpha-glucosidase inhibitor for the treatment ofdiabetes mellitus.

[0020] According to one aspect, the invention features the combinationof a PPAR modulator, preferably a PPAR δ agonist, and an SGLT inhibitor,preferably an SGLT 2 inhibitor or a selective SGLT 2 inhibitor.

[0021] A. Terms

[0022] Some terms are defined below and by their usage throughout thisdisclosure.

[0023] Unless otherwise noted, “alkyl” and “alkoxy” as used herein,whether used alone or as part of a substituent group, include straight,cyclic, and branched-chain alkyl having 1 to 8 carbon atoms, or anynumber within this range. For example, alkyl radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,2-butenyl, 2-butynyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl,2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxyradicals are oxygen ethers formed from the previously described straightor branched chain alkyl groups. The alkyl and alkoxy group may beindependently substituted with one to five, preferably one to threegroups selected from halogen (F, Cl, Br, I), oxo, OH, amino, carboxyl,and alkoxy. The alkyl and alkoxy group may also be independently linkedto one or more PEG radicals (polyethylene glycol).

[0024] The term “acyl” as used herein, whether used alone or as part ofa substituent group, means an organic radical having 2 to 6 carbon atoms(branched or straight chain) derived from an organic acid by removal ofthe hydroxyl group. The acyl group is, for example, an optionallysubstituted C₂₋₂₀ alkanoyl group, a lower alkoxy-lower alkanoyl group,an optionally substituted lower alkoxycarbonyl group, an optionallysubstituted benzoyl group, an optionally substituted phenoxycarbonylgroup, or an amino acid residue which is obtained by removing a hydroxygroup from the carboxyl group of a corresponding amino acid (whereinamino groups and/or carboxyl groups in said residue may be protected bya conventional protecting group). The term “Ac” as used herein, whetherused alone or as part of a substituent group, means acetyl.

[0025] “Aryl” is a carbocyclic aromatic radical including, but notlimited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclicaromatic radical may be substituted by independent replacement of 1 to 3of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro,amino, cyano, optionally substituted C₁-C₈-alkyl, optionally substitutedalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino,di(C₁-C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—. Illustrative aryl radicals include, for example, phenyl,naphthyl, biphenyl, indenep

[0026]

[0027] indane

[0028]

[0029] fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl,carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl,acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph”or “PH” denotes phenyl.

[0030] The term “heteroaryl” as used herein represents a stable five orsix-membered monocyclic or bicyclic aromatic ring system which consistsof carbon atoms and from one to three heteroatoms selected from N, O andS. The heteroaryl group may be attached at any heteroatom or carbonatom, which results in the creation of a stable structure. Examples ofheteroaryl groups include, but are not limited to benzofuranyl,benzothiophenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl,benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl or quinolinyl. Prefered heteroaryl groups includepyridinyl, thiophenyl, furanyl, and quinolinyl. When the heteroarylgroup is substituted, the heteroaryl group may have one to threesubstituents which are independently selected from halogen, OH, CN,mercapto, nitro, amino, cyano, optionally substituted C₁-C₈-alkyl,optionally substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkyl-amino, di(C₁-C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—.

[0031] The terms “heterocycle,” “heterocyclic,” and “heterocyclyl” referto an optionally substituted, fully or partially saturated cyclic groupwhich is, for example, a 4- to 7-membered monocyclic, 7- to 11-memberedbicyclic, or 10- to 15-membered tricyclic ring system, which has atleast one heteroatom in at least one carbon atom containing ring. Eachring of the heterocyclic group containing a heteroatom may have 1, 2, or3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The nitrogen atoms may optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom.

[0032] Exemplary monocyclic heterocyclic groups include pyrrolidinyl;oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl;oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl;tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl;2-oxopiperid inyl; 2-oxopyrrolid inyl; 4-piperidonyl; tetrahydropyranyl;tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl;thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone;1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; and the like. Exemplarybicyclic heterocyclic groups include quinuclidinyl;tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl); dihyd robenzofu ryl; dihyd robenzothienyl; dihyd robenzothiopyranyl; dihyd robenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl;tetrahydroquinolinyl; and the like. When the heteroaryl group issubstituted, the heterocyclyl may be independently substituted with oneto five, preferably one to three groups selected from halogen, OH, CN,mercapto, nitro, amino, cyano, optionally substituted C₁-C₈-alkyl,optionally substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkyl-amino, di(C₁-C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—,—CONH₂, alkyl—O—CO—O—, oralkyl-CO—NH—.

[0033] The term “composition” is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationsof the specified ingredients in the specified amounts.

[0034] The term “combined administration” includes co-administrationwherein: 1) the two or more agents are administered to a subject atsubstantially similar times; and 2) the two or more agents areadministered to a subject at different times, at independent intervalswhich may or may not overlap or coincide.

[0035] The term “subject” as used herein, refers to an animal,preferably a mammal, most preferably a human, who is the object oftreatment, observation or experiment.

[0036] The term “RXR modulator” as used herein, refers to Retinoid-Xreceptor agonists, partial agonists, or antagonists. Preferably themodulator increases insulin sensitivity. According to one aspect, themodulator is an RXR agonist.

[0037] Diabetes, Syndrome X, and associated symptoms or complicationsinclude such conditions as IDDM, NIDDM, IGT, IFG, obesity, nephropathy,neuropathy, retinopathy, atherosclerosis, polycystic ovary syndrome,polycystic ovarian syndrome, hypertension, ischemia, stroke, heartdisease, irritable bowel disorder, inflammation, and cataracts. Examplesof a prediabetic state includes IGT and IFG.

[0038] Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term ““jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated by the modulation of glucosereabsorption activity or RXR activity or both. Thus, the presentinvention provides combinations of two or more drugs wherein, forexample, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

[0039] The term “protecting groups” refer to those moieties known in theart that are used to mask functional groups; protecting groups may beremoved during subsequent synthetic transformations or by metabolic orother in vivo administration conditions. During any of the processes forpreparation of the compounds of the present invention, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973;and T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, 1999. The protecting groupsmay be removed at a convenient subsequent stage using methods known inthe art. Examples of hydroxyl and diol protecting groups are providedbelow.

[0040] Protection for the hydroxyl group includes methyl ethers,substituted methyl thers, substituted ethyl ethers, substitute benzylethers, and silyl ethers.

[0041] Substituted Methyl Ethers

[0042] Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahyd ropyranyl, tetrahyd rothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahyd ropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

[0043] Substituted Ethyl Ethers

[0044] Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, and polyethyleneglycol ethers.

[0045] Substituted Benzyl Ethers

[0046] Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyld iphenylmethyl,p-methoxyphenyidiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(/midazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

[0047] Silyl Ethers

[0048] Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyidiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

[0049] Esters

[0050] In addition to ethers, a hydroxyl group may be protected as anester. Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate), and polyethyleneglycol esters.

[0051] Carbonates

[0052] Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, methyldithiocarbonate, and polyethyleneglycol carbonates.

[0053] Assisted Cleavage

[0054] Examples of assisted cleavage include 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

[0055] Miscellaneous Esters

[0056] Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

[0057] Sulfonates

[0058] Examples of sulfonates include sulfate,methanesulfonate(mesylate), benzylsulfonate, and tosylate.

PROTECTION FOR 1,2- AND 1,3-DIOLS

[0059] Cyclic Acetals and Ketals

[0060] Examples of cyclic acetals and ketals include methylene,ethylidene, 1-t-butylethylidene, 1-phenylethylidene,(4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide(isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene,benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene,3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.

[0061] Cyclic Ortho Esters

[0062] Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

[0063] Silyl Derivatives

[0064] Examples of silyl derivatives include di-t-butylsilylene group,and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

[0065] B. Glucose Reabsorption Inhibitors

[0066] One method of treating hyperglycemia is to excrete excessiveglucose directly into urine so that the blood glucose concentration isnormalized. For example, sodium-glucose cotransporters (SGLTs),primarily found in chorionic membrane of the intestine and the kidney,are a family of proteins actively involved in the normal process ofglucose absorption. Among them, SGLT1 is present in intestinal and renalepithelial cells (Lee et al., 1994), whereas SGLT2 is found in theepithelium of the kidney (You et al., 1995, MacKenzie et al., 1994).Glucose absorption in the intestine is primarily mediated by SGLT1, ahigh-affinity low-capacity transporter with a Na⁺:glucose transportratio of 2:1. SGLT2, also known as SAAT1, transports Na⁺ and glucose ata ratio of 1:1 and functions as a low-affinity high-capacitytransporter. These SGLTs are characterized in Table 1: TABLE 1 PreferredK_(m)* TmG** K_(m)* ISOFORM TISSUE Stoichiometry Substrate in vitro invitro In vivo SGLT1 Sm. Intestine 2:1 D-glucose 0.1 nd Nd D-galactoseKidney (S1, S3) 2:1 D-glucose 0.39 7.9 0.3 D-galactose SGLT2 Kidney (S3)1:1 D-glucose 1.64 83 6 (SAAT1)

[0067] Renal reabsorption of glucose is mediated by SGLT1 and SGLT2(Silverman et al., 1992; Deetjen et al., 1995). Plasma glucose isfiltered in the glomerulus and is transepithelially reabsorbed in theproximal tubules. SGLT1 and SGLT2 are located in the apical plasmamembranes of the epithelium and derive their energy from the inwardsodium gradient created by the Na⁺/K⁺ ATPase pumps located on thebasolateral membrane. Once reabsorbed, the elevated cytosolic glucose isthen transported to the interstitial space by facilitated glucosetransports (GLUT1 and GLUT2). Therefore, inhibition of SGLTs reducesplasma glucose through suppression of glucose reabsorption in thekidney. A therapeutically or prophylactically effective amount of anSGLT inhibitor, such as that sufficient to increase urine glucoseexcretion, or to decrease plasma glucose, in a subject by a desiredamount per day, can be readily determined using methods established inthe art. Recently, it has been found that phlorizin, a natural glycosidepresent in barks and stems of Rosaceae (e.g., apple, pear, etc.),inhibits Na⁺-glucose co-transporters located in chorionic membrane ofthe intestine and the kidney. By inhibiting Na⁺-glucose co-transporteractivity, phlorizin inhibits the renal tubular glucose reabsorption andpromotes the excretion of glucose so that the glucose level in a plasmais controlled at a normal level for a long time via subcutaneous dailyadministration (Journal of Clinical Investigation, 1987, Vol. 79, p.1510).

[0068] JP 8-347406, filed Dec. 26, 1996, and U.S. Pat. Nos. 5,767,094,5,830,873, and 6,048,842 (all to Tanabe Seiyaku Co., Ltd.) disclosepropiophenone derivatives having hypoglycemic activity by inhibitingsodium-glucose cotransporter activity. JP2762903, JP2795162, JP2906978,and U.S. Pat. Nos. 5,424,406 and 5,731,292, all to Tanabe Seiyaku Co.,Ltd., disclose dihydrochalcone derivatives having hypoglycemic activitybased on the urine glucose increasing activity thereof.

[0069] In particular, U.S. Pat. No. 6.048.842 discloses a compound, or apharmaceutically acceptable salt thereof, useful for treatment and/orprophylaxis of diabetes, which has the structure of Formula I:

[0070] wherein OX is a hydroxy group which may optionally be protected,Y is a lower alkyl group, and Z is a β-D-glucopyranosyl group whereinone or more hydroxy groups may optionally be protected.

[0071] Where OX of Formula I is a protected hydroxy group, theprotecting group may be any protecting group which can be a protectinggroup for a phenolic hydroxy group, for example, a lower alkoxy-loweralkyl group such as methoxymethyl group; an allyl group; and an acylgroup such as a lower alkanoyl group, a lower alkoxy-lower alkanoylgroup, a lower alkoxycarbonyl group, a lower alkoxy-lower alkoxycarbonylgroup, an arylcarbonyl group (e.g., benzoyl group). Among theseprotecting groups, preferable ones are an acyl group such as a loweralkanoyl group, a lower alkoxy-lower alkanoyl group, a loweralkoxycarbonyl group, a lower alkoxy-lower alkoxycarbonyl group, andespecially preferable ones are a lower alkanoyl group, and a loweralkoxycarbonyl group.

[0072] Where Z of Formula I is a β-D-glucopyranosyl group wherein one ormore hydroxy groups are protected, the protecting group may be anyconventional protecting groups for hydroxy group which can easily beremoved by a conventional method such as acid-treatment, hydrolysis,reduction, etc. The β-D-glucopyranosyl group wherein one or more hydroxygroups are protected by the above-mentioned protecting groups may beselected from (i) a β-D-glucopyranosyl group wherein one or more hydroxygroups are acylated, (ii) a β-D-glucopyranosyl group wherein two hydroxygroups combine to form a 1-lower alkoxy-lower alkylidenedioxy group, abenzylidenedioxy group, a phosphinicodioxy group, or a carbonyidioxygroup together with the protecting groups thereof, and (iii) aβ-D-glucopyranosyl group wherein one or two hydroxy groups are acylated,and the other two hydroxy groups combine to form a 1-lower alkoxy-loweralkylidenedioxy group, a benzylidenedioxy group, a phosphinicodioxygroup, or a carbonyldioxy group together with the protecting groupsthereof. However, the protecting groups for the hydroxy groups of theβ-D-glucopyranosyl group should not be construed to be limited to theabove protecting groups, and may be any ones which can be removed afteradministering the present compound into the living body and give thehydroxy groups of the β-D-glucopyranosyl group, or can promote theabsorption of the desired compound into the living body, or make it moreeasy to administer the present compound into the living body, or canincrease the solubility in oil and/or water of the present compound.

[0073] When the hydroxy group of the β-D-glucopyranosyl group isacylated, the acyl group is preferably a lower alkanoyl group, a loweralkoxy-lower alkanoyl group, a lower alkoxycarbonyl group, a loweralkoxy-lower alkoxycarbonyl group, or an arylcarbonyl group (e.g.,benzoyl group), or an amino acid residue which is obtained by removing ahydroxy group from the carboxyl group of a corresponding amino acid(wherein amino groups and/or carboxyl groups and/or hydroxy groups insaid residue may be protected by a conventional protecting group). Theamino acid residue includes a group which is obtained by removing ahydroxy group from the carboxyl group of a natural amino acid such asaspartic acid, glutamic acid, glutamine, serine, sarcosine, proline,phenylalanine, leucine, isoleucine, glycine, tryptophan, cysteine,histidine, tyrosine, or valine, or an antipode thereof, or a racemiccompound thereof.

[0074] When Z is a β-D-glucopyranosyl group wherein two hydroxy groupsof the β-D-glucopyranosyl group combine to form a 1-lower alkoxy-loweralkylidenedioxy group, a benzylidenedioxy group, a phosphinicodioxygroup, or a carbonyidioxy group together with the protecting groupsthereof, said β-D-glucopyranosyl group may be a β-D-glucopyranosyl groupwherein the 4- and 6-hydroxy groups of the β-D-glucopyranosyl groupcombine to form a 1-lower alkoxy-lower alkylidenedioxy group, abenzylidenedioxy group, a phosphinicodioxy group, or a carbonyidioxygroup together with the protecting groups thereof. SuchP-D-glucopyranosyl group has one of the following two formulae:

[0075] wherein one of R⁷ and R⁸ is a hydrogen atom or a lower alkylgroup, and the other is a lower alkoxy group, or one of R⁷ and R⁸ is ahydrogen atom, and the other is a phenyl group, or R⁷ and R⁸ combine toform an oxo group.

[0076] When two hydroxy groups of the β-D-glucopyranosyl group combineto form a 1-lower alkoxy-lower alkylidenedioxy group together with theprotecting groups thereof, the 1-lower alkoxy-lower alkylidenedioxygroup is preferably a 1-lower alkoxyethylidenedioxy group, and morepreferably a 1-methoxyethylidenedioxy group or a 1-ethoxyethylidenedioxygroup.

[0077] Y of Formula I is preferably an alkyl group having 1 to 4 carbonatoms, more preferably a methyl group or an ethyl group.

[0078] The propiophenone derivatives of Formula I or a pharmaceuticallyacceptable salt thereof include an intramolecular salt thereof, or asolvate or hydrate thereof, as well.

[0079] In addition, U.S. Pat. No. 5,830,873 discloses a compound, or apharmaceutically acceptable salt thereof, useful for treatment and/orprophylaxis of diabetes which has the structure of Formula II:

[0080] wherein X is an oxygen atom, a sulfur atom or a methylene group,OY is a protected or unprotected hydroxy group, Z is aβ-D-glucopyranosyl group or 4-O-(α-D-glucopyranosyl)-β-D-glucopyranosylgroup wherein one or more hydroxy groups of these groups may optionallybe acylated, and the dotted line means the presence or absence of adouble bond.

[0081] Furthermore, U.S. Pat. No. 5,767,094 discloses a compound, or apharmaceutically acceptable salt thereof, useful for treatment and/orprophylaxis of diabetes which has the structure of Formula III:

[0082] wherein R′ is a lower alkanoyl group, and R″ is a hydrogen atom,or R′ is a hydrogen atom, and R″ is a lower alkoxycarbonyl group.

[0083] Furthermore, U.S. Pat. Nos. 5,424,406 and 5,731,292 disclose acompound, or a pharmaceutically acceptable salt thereof, useful fortreatment and/or prophylaxis of diabetes which has the structure ofFormula IV:

[0084] wherein Ar is an aryl group, R¹ is hydrogen atom or an acylgroup, R² is hydrogen atom, an acyl group or α-D-glucopyranosyl group,or R¹ and R² may combine together to form a substituted methylene group,R³ and R⁴ are each hydrogen atom or an acyl group, and OR⁵ is aprotected or unprotected hydroxy group or a lower alkoxy group.

[0085] Other SGLT inhibitors include alkyl- and phenyl-glucosides,1-5-isoquinolinesulfonyl)-2-methylpiperazine-HCl (indirectly via proteinkinase C), p-chloromercuribenzoate (PCMB), N,N′-dicyclohexylcarbodiimide(DCCD), copper and cadmium ions, and trivalent lanthanides.

[0086] The compounds of formulae I, II, III, IV, and V may be preparedby the processes disclosed in U.S. Pat. Nos. 5,424,406, 5,731,292,5,767,094, 5,830,873, and 6,048,842.

[0087] C. RXR Modulators

[0088] Retinoid-X receptor (RXR) modulators are also insulin sensitizingdrugs, which include, but are not limited to:

[0089] (1) bexarotene(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoicacid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as LGD 1069,LG 100069, LG 1069, LDG 1069, LG 69, RO 264455);

[0090] (2) 9-cis-retinoic acid;

[0091] (3) AGN-4326 (also known as ALRT-4204, AGN-4204, ALRT-326,ALRT-324, or LGD 1324);

[0092] (4) LGD 1324 (ALRT 324);

[0093] (5) LG 100754;

[0094] (6) LY-510929;

[0095] (7) LGD 1268(6-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-ylcycloprop-1-yl)nicotinicacid, known as ALRT 268 or LG 100268);

[0096] (8) LG 100264; and

[0097] (9) substituted heterocycles such as compounds of Formula VI,

[0098] wherein

[0099] n and m are independently 0 or 1;

[0100] R₁ and R₂ are 1) independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, alkoxy, substituted alkoxy, hydroxyl, acyl, amino,mono-substituted amino, di-substituted amino, carboxy, carboalkoxy,alkylcarboxamide, dialkylcarboxamide or haloalkoxy; or 2) R₁ and R₂together with the aromatic ring bonded thereto form a cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl residuethat may optionally comprise 1 or 2 heteroatoms selected from O, S, NHor N-alkyl;

[0101] R₃ and R₄ are independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylsulfonamide,arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate,heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkoxy; carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide;

[0102] A is —CR₆R₇— wherein R₆ and R₇ are independently or togetherhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,haloalkoxy; or R₆ and R₇ together form a cycloalkyl residue that mayoptionally comprise 1 or 2 heteroatoms selected from O, S, NH orN-alkyl;

[0103] Ar is Formula VII, VIII, IX or X:

[0104] wherein R₈, R₉ and R₁₀ are independently or together hydrogen,alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy,amino, mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkoxy; carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide;

[0105] R₅ is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;

[0106]

represents a bond present or absent; and

[0107] W, X, Y and Z are independently or together —C(O)—, —C(S)—, —S—,—O—, or —NH— residues.

[0108] One preferred example of compounds of Formula VI is MX-6054,which is 2,4-thiazolidinedione,5-[[3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-4-(trifluoromethoxy)phenyl]methylene]-,(5Z)-, also named 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,represented by the following formula:

[0109] Other preferred examples of RXR modulators include compounds ofFormula VI wherein the group

[0110]

[0111] is 2,4-thiazolidinedione

[0112]

[0113] 2-thioxo-4-thiazolidinedione

[0114]

[0115] isoxazolidinedione

[0116]

[0117] 2,4-imidazolidinedione

[0118]

[0119] or 2,4-thioxo-4-imidazolidinedione

[0120]

[0121] When n is 1, preferably R₁ and R₂ together with the aromatic ringbonded thereto form a substituted cycloalkyl optionally comprising 1 or2 heteroatoms selected from O, S, NH or N-alkyl, and R₃ is alkyl orsubstituted alkyl. Also preferably, A is —CR₆R₇— wherein R₆ and R₇ areindependently or together alkyl; or R₆ and R₇ together form a cycloalkylcomprising 1 or 2 oxygen atoms and more preferably a 1,3-dioxolane ring.Still preferably, the group

[0122]

[0123] is 2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione,isoxazolidinedione, 2,4-imidazolidinedione or2,4-thioxo-4-imidazolidinedione.

[0124] Preferably, compounds of Formula VI are selected from:

[0125]3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione;

[0126]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4-thiazolidinedione;

[0127]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4-thiazolidinedione;

[0128]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo-2,4-thiazolidinedione;

[0129]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo-2,4-thiazolidinedione;

[0130]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo-2,4-imidazolidinedione;

[0131]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo-2,4-imidazolidinedione;

[0132]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4-imidazolidinedione;

[0133]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4-imidazolidinedione;

[0134]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4-thiazolidinedione;

[0135]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4-thiazolidinedione;

[0136]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-2,4-thiazolidinedione;

[0137]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo-2,4-thiazolidinedione;

[0138]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-2,4-imidazolidinedione;

[0139]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo-2,4-imidazolidinedione;

[0140]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4-imidazolidinedione;and

[0141]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4-imidazolidinedione.

[0142] These and other RXR modulators are disclosed in WO 0116122 and WO0116123, to Maxia Pharmaceuticals, Inc. These publications also describematerials of making and using the disclosed RXR modulators and areincorporated herein by reference.

[0143] D. Additional Antidiabetic Agents

[0144] Antidiabetic agents that can be used as a third antidiabeticagent according to the invention include, but are not limited to:

[0145] (A) Thiazolidinediones and non-thiazolidinediones insulinsensitizers, which decrease peripheral insulin resistance by enhancingthe effects of insulin at target organs and tissues.

[0146] Some of these drugs are known to bind and activate the nuclearreceptor peroxisome proliferator-activated receptor-gamma (PPARγ) whichincreases transcription of specific insulin-responsive genes. Examplesof PPAR-gamma agonists are thiazolidinediones such as:

[0147] (1) rosiglitazone(2,4-thiazolidinedione,5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-,(Z)-2-butenedioate (1:1) or5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione,known as AVANDIA; also known as BRL 49653, BRL 49653C, BRL 49653C, SB210232, or rosiglitazone maleate);

[0148] (2) pioglitazone (2,4-thiazolidinedione,5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-, monohydrochloride,(+−)-or5-((4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)methy)-2,4-thiazolidinedione,known as ACTOS, ZACTOS, or GLUSTIN; also known as AD 4833, U 72107, U72107A, U 72107E, pioglitazone hydrochloride (USAN));

[0149] (3) troglitazone(5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-2,4-thiazolidinedione, knownas NOSCAL, REZULIN, ROMOZIN, or PRELAY; also known as Cl 991, CS 045, GR92132, GR 92132X);

[0150] (4) isaglitazone((+)-5-[[6-[(2-fluorophenyl)methoxy]-2-naphthalenyl]methyl]-2,4-thiazolidinedioneor5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl-2,4-thiazolidinedioneor 5-(6-(2-fluorobenzyloxy)naphthalen-2-ylmethyl)thiazolidine-2,4-dione,also known as MCC-555 or neoglitazone); and

[0151] (5) 5-BTZD.

[0152] Additionally, the non-thiazolidinediones that act as insulinsensitizing agents include, but are not limited to:

[0153] (1) JT-501 (JTT 501, PNU-1827, PNU-716-MET-0096, or PNU 182716:isoxazolidine-3,5-dione,4-((4-(2-phenyl-5-methyl)-1,3-oxazolyl)ethylphenyl-4)methyl-);

[0154] (2) KRP-297(5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-(trifluoromethyl)benzyl)benzamide or5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide);and

[0155] (3) Farglitazar (L-tyrosine,N-(2-benzoylphenyl)-o-(2-(5-methyl-2-phenyl -4-oxazolyl)ethyl)- orN-(2-benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-L-tyrosine,or GW2570 or GI-262570).

[0156] Other agents have also been shown to have PPAR modulator activitysuch as PPARγ, SPPARγ, and/or PPARα/δ agonist activity. Examples arelisted below: (1) AD 5075;

[0157] (2) R 119702 ((+−)-5-(4-(5-Methoxy-1H-benzimidazol-2-ylmethoxy)benzyl)thiazolin-2,4-dione hydrochloride, orCl 1037 or CS 011);

[0158] (3) CLX-0940 (peroxisome proliferator-activated receptor alphaagonist/peroxisome proliferator-activated receptor gamma agonist);

[0159] (4) LR-90 (2,5,5-tris(4-chlorophenyl)-1,3-dioxane-2-carboxylicacid, PPAR α/γ agonist);

[0160] (5) Tularik (PPAR γ agonist);

[0161] (6) CLX-0921 (PPAR γ agonist);

[0162] (7) CGP-52608 (PPAR agonist);

[0163] (8) GW-409890 (PPAR agonist);

[0164] (9) GW-7845 (PPAR agonist);

[0165] (10) L-764406 (PPAR agonist);

[0166] (11) LG-101280 (PPAR agonist);

[0167] (12) LM-4156 (PPAR agonist);

[0168] (13) Risarestat (CT-112);

[0169] (14) YM 440 (PPAR agonist);

[0170] (15) AR-H049020 (PPAR agonist);

[0171] (16) GW 0072(4-(4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazolidinyl)butyl)benzoicacid);

[0172] (17) GW 409544 (GW-544 or GW-409544);

[0173] (18) NN 2344 (DRF 2593);

[0174] (19) NN 622 (DRF 2725);

[0175] (20) AR-H039242 (AZ-242);

[0176] (21) GW 9820 (fibrate);

[0177] (22) GW 1929(N-(2-benzoylphenyl)-O-(2-(methyl-2-pyridinylamino)ethyl)-L-tyrosine,known as GW 2331, PPAR α/65 agonist);

[0178] (23) SB 219994((S)-4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)benzenepropanoicacid or3-(4--(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2(S)-(2,2,2-trifluoroethoxy)propionicacid or benzenepropanoic acid,4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)-,(alphaS)-, PPAR ═/65 agonist);

[0179] (24) L-796449 (PPAR αγ agonist);

[0180] (25) Fenofibrate (Propanoic acid,2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-, 1-methylethyl ester, known asTRICOR, LIPCOR, LIPANTIL, LIPIDIL MICRO PPAR α agonist);

[0181] (26) GW-9578 (PPAR α agonist);

[0182] (27) GW-2433 (PPAR α/γ agonist);

[0183] (28) GW-0207 (PPAR γ agonist);

[0184] (29) LG-100641 (PPAR γ agonist);

[0185] (30) LY-300512 (PPAR γ agonist);

[0186] (31) NID525-209 (NID-525);

[0187] (32) VDO-52 (VDO-52);

[0188] (33) LG 100754 (peroxisome proliferator-activated receptoragonist);

[0189] (34) LY-510929 (peroxisome proliferator-activated receptoragonist);

[0190] (35) bexarotene(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoicacid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as LGD 1069,LG 100069, LG 1069, LDG 1069, LG 69, RO 264455); and

[0191] (36) GW-1536 (PPAR α/γ agonist).

[0192] (B) Other insulin sensitizing agents include, but are not limitedto:

[0193] (1) INS-1 (D-chiro inositol orD-1,2,3,4,5,6-hexahydroxycyclohexane);

[0194] (2) protein tyrosine phosphatase 1 B (PTP-1B) inhibitors;

[0195] (3) glycogen synthase kinase-3 (GSK3) inhibitors;

[0196] (4) beta 3 adrenoceptor agonists such as ZD 2079((R)—N-(2-(4-(carboxymethyl)phenoxy)ethyl)-N-(2-hydroxy-2-phenethyl)ammonium chloride, also known as ICI D 2079) or AZ 40140;

[0197] (5) glycogen phosphorylase inhibitors;

[0198] (6) fructose-1,6-bisphosphatase inhibitors;

[0199] (7) chromic picolinate, vanadyl sulfate (vanadium oxysulfate);

[0200] (8) KP 102 (organo-vanadium compound);

[0201] (9) chromic polynicotinate;

[0202] (10) potassium channel agonist NN 414;

[0203] (11) YM 268 (5,5′-methylene-bis(1,4-phenylene) bismethylenebis(thiazolidine-2,4-dione);

[0204] (12) TS 971;

[0205] (13) T 174((+−)-5-(2,4-dioxothiazolidin-5-ylmethyl)-2-(2-naphthylmethyl)benzoxazole);

[0206] (14) SDZ PGU 693((+)-trans-2(S-((4-chlorophenoxy)methyl)-7alpha-(3,4-dichlorophenyl)tetrahydropyrrolo(2,1-b)oxazol-5(6H)-one);

[0207] (15) S 15261 ((−)-4-(2-((9H-fluoren-9-ylacetyl)amino)ethyl)benzoic acid2-((2-methoxy-2-(3-(trifluoromethyl)phenyl)ethyl)amino)ethyl ester);

[0208] (16) AZM 134 (Alizyme);

[0209] (17) ARIAD;

[0210] (18) R 102380;

[0211] (19) PNU 140975 (1-(hydrazinoiminomethyl)hydrazino)acetic acid;

[0212] (20) PNU 106817 (2-(hydrazinoiminomethyl)hydrazino)acetic acid;

[0213] (21) NC 2100(5-((7-(phenylmethoxy)-3-quinolinyl)methyl)-2,4-thiazolidinedione;

[0214] (22) MXC 3255;

[0215] (23) MBX 102;

[0216] (24) ALT 4037;

[0217] (25) AM 454;

[0218] (26) JTP 20993 (2-(4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)benzyl)-malonic acid dimethyl diester);

[0219] (27) Dexlipotam (5(R)-(1,2-dithiolan-3-yl)pentanoic acid, alsoknown as (R)-alpha lipoic acid or (R)-thioctic acid);

[0220] (28) BM 170744 (2,2-Dichloro-12-(p-chlorophenyl) dodecanoicacid);

[0221] (29) BM 152054 (5-(4-(2-(5-methyl-2-(2-thienyl)oxazol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazolidine-2,4-dione);

[0222] (30) BM 131258 (5-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzothien -7-ylmethyl)thiazolidine-2,4-dione);

[0223] (31) CRE 16336 (EML 16336);

[0224] (32) HQL 975 (3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2(S)-(propylamino)propionic acid);

[0225] (33) DRF 2189 (5-((4-(2-(1-Indolyl)ethoxy)phenyl)methyl)thiazolidine-2,4-dione);

[0226] (34) DRF 554158;

[0227] (35) DRF-NPCC;

[0228] (36) CLX 0100, CLX 0101, CLX 0900, or CLX 0901;

[0229] (37) IkappaB Kinase (IKK B) Inhibitors

[0230] (38) mitogen-activated protein kinase (MAPK) inhibitors p38 MAPKStimulators

[0231] (39) phosphatidyl-inositide triphosphate

[0232] (40) insulin recycling receptor inhibitors

[0233] (41) glucose transporter 4 modulators

[0234] (42) TNF-α antagonists

[0235] (43) plasma cell differentiation antigen-1 (PC-1) Antagonists

[0236] (44) adipocyte lipid-binding protein (ALBP/aP2) inhibitors

[0237] (45) phosphoglycans

[0238] (46) Galparan;

[0239] (47) Receptron;

[0240] (48) islet cell maturation factor;

[0241] (49) insulin potentiating factor (IPF or insulin potentiatingfactor-1);

[0242] (50) somatomedin C coupled with binding protein (also known asIGF-BP3, IGF-BP3, SomatoKine);

[0243] (51) Diab II (known as V-411) or Glucanin, produced by BiotechHoldings Ltd. or Volque Pharmaceutical;

[0244] (52) glucose-6 phosphatase inhibitors;

[0245] (53) fatty acid glucose transport protein;

[0246] (54) glucocorticoid receptor antagonists; and

[0247] (55) g lutamine:fructose-6-phosphate amidotransferase (G FAT)modulators.

[0248] (C) Biguanides, which decrease liver glucose production andincreases the uptake of glucose. Examples include mefformin such as:

[0249] (1) 1,1-dimethylbiguanide (e.g., Mefformin-DepoMed,Mefformin-Biovail Corporation, or METFORMIN GR (metformin gastricretention polymer)); and

[0250] (2) metformin hydrochloride (N,N-dimethylimidodicarbonimidicdiamide monohydrochloride, also known as LA 6023, BMS 207150,GLUCOPHAGE, or GLUCOPHAGE XR.

[0251] (D) Alpha-glucosidase inhibitors, which inhibitalpha-glucosidase. Alpha-glucosidase converts fructose to glucose,thereby delaying the digestion of carbohydrates. The undigestedcarbohydrates are subsequently broken down in the gut, reducing thepost-prandial glucose peak. Examples include, but are not limited to:

[0252] (1) acarbose (D-glucose,O-4,6-dideoxy-4-(((1S-(1alpha,4alpha,5beta,6alpha))-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-,also known as AG-5421, Bay-g-542, BAY-g-542, GLUCOBAY, PRECOSE, GLUCOR,PRANDASE, GLUMIDA, or ASCAROSE);

[0253] (2) Miglitol (3,4,5-piperidinetriol,1-(2-hydroxyethyl)-2-(hydroxymethyl) -, (2R (2alpha, 3beta, 4alpha,5beta))- or(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl-3,4,5-piperidinetriol,also known as BAY 1099, BAY M 1099, BAY-m-1099, BAYGLITOL, DIASTABOL,GLYSET, MIGLIBAY, MITOLBAY, PLUMAROL);

[0254] (3) CKD-711(0-4-deoxy-4-((2,3-epoxy-3-hydroxymethyl-4,5,6-trihydroxycyclohexane-1-yl)amino)-alpha-b-glucopyranosyl-(1-4)-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose);

[0255] (4) emiglitate(4-(2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl)ethoxy)benzoicacid ethyl ester, also known as BAY o 1248 or MKC 542);

[0256] (5) MOR 14 (3,4,5-piperidinetriol, 2-(hydroxymethyl)-1-methyl-,(2R-(2alpha,3beta,4alpha,5beta)) -, also known asN-methyldeoxynojirimycin or N-methylmoranoline); and

[0257] (6) Voglibose(3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)-D-epi-inositolorD-epi-Inositol,3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)-, also known as A 71100, AO 128, BASEN, GLUSTAT, VOGLISTAT.

[0258] (E) Insulins include regular or short-acting,intermediate-acting, and long-acting insulins, non-injectable or inhaledinsulin, tissue selective insulin, glucophosphokinin (D-chiroinositol),insulin analogues such as insulin molecules with minor differences inthe natural amino acid sequence and small molecule mimics of insulin(insulin mimetics), and endosome modulators. Examples include, but arenot limited to:

[0259] (1) Biota;

[0260] (2) LP 100;

[0261] (3) (SP-5-21)-oxobis (1-pyrrolidinecarbodithioato-S,S′) vanadium,

[0262] (4) insulin aspart (human insulin (28B-L-aspartic acid) orB28-Asp-insulin, also known as insulin X14, INA-X14, NOVORAPID, NOVOMIX,or NOVOLOG);

[0263] (5) insulin detemir (Human29B-(N6-(1-oxotetradecyl)-L-lysine)-(1A-21A), (1B-29B)-Insulin or NN304);

[0264] (6) insulin lispro (″28B-L-lysine-29B-L-proline human insulin, orLys(B28), Pro(B29) human insulin analog, also known as lys-pro insulin,LY 275585, HUMALOG, HUMALOG MIX 75/25, or HUMALOG MIX 50/50);

[0265] (7) insulin glargine (human (A21-glycine, B31-arginine,B32-arginine) insulin HOE 901, also known as LANTUS, OPTISULIN);

[0266] (8) Insulin Zinc Suspension, extended (Ultralente), also known asHUMULIN U or ULTRALENTE;

[0267] (9) Insulin Zinc suspension (Lente), a 70% crystalline and 30%amorphous insulin suspension, also known as LENTE ILETIN II, HUMULIN L,or NOVOLIN L;

[0268] (10) HUMULIN 50/50 (50% isophane insulin and 50% insulininjection);

[0269] (11) HUMULIN 70/30 (70% isophane insulin NPH and 30% insulininjection), also known as NOVOLIN 70/30, NOVOLIN 70/30 PenFill, NOVOLIN70/30 Prefilled;

[0270] (12) insulin isophane suspension such as NPH ILETIN II, NOVOLINN, NOVOLIN N PenFill, NOVOLIN N Prefilled, HUMULIN N;

[0271] (13) regular insulin injection such as ILETIN II Regular, NOVOLINR, VELOSULIN BR, NOVOLIN R PenFill, NOVOLIN R Prefilled, HUMULIN R, orRegular U-500 (Concentrated);

[0272] (14) ARIAD;

[0273] (15) LY 197535;

[0274] (16) L-783281; and

[0275] (17) TE-17411.

[0276] (F) Insulin secretion modulators such as:

[0277] (1) glucagon-like peptide-1 (GLP-1) and its mimetics;

[0278] (2) glucose-insulinotropic peptide (GIP) and its mimetics;

[0279] (3) exendin and its mimetics;

[0280] (4) dipeptyl protease (DPP or DPPIV) inhibitors such as

[0281] (4a) DPP-728 or LAF 237(2-pyrrolidinecarbonitrile,1-(((2-((5-cyano-2-pyridinyl)amino)ethyl)amino)acetyl),known as NVP-DPP-728, DPP-728A, LAF-237);

[0282] (4b) P 3298 or P32/98 (di-(3N-((2S,3S)-2-amino-3-methyl-pentanoyl)-1,3-thiazolidine)fumarate);

[0283] (4c) TSL 225(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid);

[0284] (4d) Valine pyrrolidide (valpyr);

[0285] (4e) 1-aminoalkylisoquinolinone-4-carboxylates and analoguesthereof;

[0286] (4f) SDZ 272-070 (1-(L-Valyl)pyrrolidine);

[0287] (4g) TMC-2A, TMC-2B, or TMC-2C;

[0288] (4h) Dipeptide nitriles (2-cyanopyrrolodides);

[0289] (4i) CD26 inhibitors; and

[0290] (4j) SDZ 274-444;

[0291] (5) glucagon antagonists such as AY-279955; and

[0292] (6) amylin agonists which include, but are not limited to,pramlintide (AC-137, Symlin, tripro-amylin or pramlintide acetate).

[0293] (G) Insulin secretagogues, which increase insulin production bystimulating pancreatic beta cells, such as:

[0294] (1) asmitiglinide((2(S)-cis)-octahydro-gamma-oxo-alpha-(phenylmethyl)-2H-isoindole-2-butanoicacid, calcium salt, also known as mituglimide calcium hydrate, KAD 1229,or S 21403);

[0295] (2) Ro 34563;

[0296] (3) nateglinide(trans-N-((4-(1-methylethyl)cyclohexyl)carbonyl)-D-phenylalanine, alsoknown as A 4166, AY 4166, YM 026, FOX 988, DJN 608, SDZ DJN608, STARLIX,STARSIS, FASTIC, TRAZEC);

[0297] (4) JTT 608 (trans-4-methyl-gamma-oxocyclohexanebutanoic acid);

[0298] (5) sulfonylureas such as:

[0299] (5a) chlorpropamide (1-[(p-chlorophenyl)sulfonyl]-3-propylurea,also known as DIABINESE);

[0300] (5b) tolazamide (TOLINASE or TOLANASE);

[0301] (5c) tolbutamide (ORINASE or RASTINON);

[0302] (5d) glyburide(1-[[p-[2-(5-chloro-o-anisamido)ethyl]phenyl]sulfonyl]-3-cyclohexylurea,also known as Glibenclamide, DIABETA, MICRONASE, GLYNASE PresTab, orDAONIL);

[0303] (5e) glipizide(1-cyclohexyl-3-[[p-[2-(5-ethylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea,also known as GLUCOTROL, GLUCOTROL XL, MINODIAB, or GLIBENESE);

[0304] (5 glimepiride (1H-pyrrole-1-carboxamide,3-ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-,trans-, also known as Hoe-490 or AMARYL);

[0305] (5g) acetohexamide (DYMELOR);

[0306] (5h) gliclazide (DIAMICRON);

[0307] (5i) glipentide (STATICUM);

[0308] (5j) gliquidone (GLURENORM); and

[0309] (5k) glisolamide (DIABENOR);

[0310] (6) K⁺ channel blockers including, but not limited to,meglitinides such as

[0311] (6a) Repaglinide((S)-2-ethoxy-4-(2-((3-methyl-1-(2-(1-piperidinyl)phenyl)butyl)amino)-2-oxoethyl)benzoicacid, also known as AGEE 623, AGEE 623 ZW, NN 623, PRANDIN, orNovoNorm);

[0312] (6b) imidazolines; and

[0313] (6c) α-2 adrenoceptor antagonists;

[0314] (7) pituitary adenylate cyclase activating polypeptide (PAcAP);

[0315] (8) vasoactive intestinal peptide (VIP);

[0316] (9) amino acid analogs; and

[0317] (10) glucokinase activators.

[0318] (H) Growth Factors such as:

[0319] (1) insulin-like growth factors (IGF-1, IGF-2);

[0320] (2) small molecule neurotrophins;

[0321] (3) somatostatin;

[0322] (4) growth hormone-releasing peptide (GHRP);

[0323] (5) growth hormone-releasing factor (GHRF); and

[0324] (6) human growth hormone fragments.

[0325] (I) Immunomodulators such as:

[0326] (1) vaccines;

[0327] (2) T-cell inhibitors

[0328] (3) monoclonal antibodies;

[0329] (4) interleukin-1 (IL-1) antagonists; and

[0330] (5) BDNF.

[0331] (J) Other antidiabetic agents:

[0332] (1) rHu-Glucagon;

[0333] (2) DHEA analogs;

[0334] (3) carnitine palmitoyl transferase (CPT) inhibitors;

[0335] (4) islet neurogenesis;

[0336] (5) pancreatic β amyloid inhibitors; and

[0337] (6) UCP (uncoupling protein)-2 and UCP-3 modulators.

[0338] In addition, a second RXR modulator, as described above inSection C, may also be utilized as a third antidiabetic agent, providedthat it is different from the first RXR modulator.

[0339] E. Combinations

[0340] The invention features a combination therapy comprisingadministering a glucose reabsorption inhibitor, such as an SGLTinhibitor, and an RXR modulator for the treatment of diabetes orSyndrome X, or associated symptoms or complications thereof. Thedemonstrated efficacy of SGLT inhibitors in numerous models of NIDDMvalidates the utility of this drug alone for the treatment of NIDDM inhumans. Since glucose reabsorption inhibitors have a mechanism of actiondistinct from that of RXR modulators, the disclosed combination with RXRmodulators has the advantage of reducing the amount of either drugnecessary to achieve combined therapeutic or pharmaceutical efficacy,relative to the use of either drug alone, thereby reducing one or moreadverse side-effects, which often include weight gain, edema, cardiachypertrophy, hepatohypertrophy, hypoglycemia, or hepatotoxicity, or anycombination thereof.

[0341] The invention provides a method for treating diabetes or SyndromeX, or complications thereof in a subject, said method comprisingadministering to said subject a jointly effective amount of a glucosereabsorption inhibitor in combination with a jointly effective amount ofan RXR modulator. In one aspect of the invention, the RXR modulator isan RXR agonist that increases insulin sensitivity in the subject. Inanother aspect of the invention, the RXR modulator is an RXR antagonistthat increases insulin sensitivity in the subject. Methods to determinethe insulin sensitizing activity of an agent are well known in the art.For example, an insulin sensitizer can increase glucose tolerance in asubject in an oral glucose tolerance test.

[0342] Particularly, the diabetes or Syndrome X, or associated symptomsor complication thereof is selected from IDDM, NIDDM, IGT, and IFG. Moreparticularly, the RXR modulator is a compound of Formula VI,

[0343] wherein R₁, R₂, R₃, R₄, R₅, A, Ar, m, n, W, X, Y, and Z are asdescribed above in Section C. Preferably, the group

[0344]

[0345] is 2,4-thiazolidinedione

[0346] 2-thioxo-4-thiazolidinedione

[0347]

[0348] isoxazolidinedione

[0349]

[0350] 2,4-imidazolidinedione

[0351]

[0352] or 2,4-thioxo-4-imidazolidinedione

[0353]

[0354] When n is 1, preferably R₁ and R₂ together with the aromatic ringbonded thereto form a substituted cycloalkyl optionally comprising 1 or2 heteroatoms selected from O, S, NH or N-alkyl, and R₃ is alkyl orsubstituted alkyl. Also preferably, A is —CR₆R₇— wherein R₆ and R₇ areindependently or together alkyl; or R₆ and R₇ together form a cycloalkylcomprising 1 or 2 oxygen atoms and more preferably a 1,3-dioxolane ring.Still preferably, the group

[0355]

[0356] is 2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione,isoxazolidinedione, 2,4-imidazolidinedione or2,4-thioxo-4-imidazolidinedione.

[0357] Preferably, compounds of Formula VI are selected from:

[0358]3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione;

[0359]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4-thiazolidinedione;

[0360]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4-thiazolidinedione;

[0361]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo-2,4-thiazolidinedione;

[0362]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo-2,4-thiazolidinedione;

[0363]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo-2,4-imidazolidinedione;

[0364]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo-2,4-imidazolidinedione;

[0365]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4-imidazolidinedione;

[0366]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4-imidazolidinedione;

[0367]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4-thiazolidinedione;

[0368]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4-thiazolidinedione;

[0369]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-2,4-thiazolidinedione;

[0370]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo-2,4-thiazolidinedione;

[0371]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-2,4-imidazolidinedione;

[0372]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo-2,4-imidazolidinedione;

[0373]4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4-imidazolidinedione;and

[0374]4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4-imidazolidinedione.

[0375] One of the preferred compounds of Formula VI is MX-6054, which is2,4-thiazolidined ione,5-[[3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-4-(trifluoromethoxy)phenyl]methylene]-,(5Z)-, also named3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,represented by the following formula:

[0376] This invention also provides a pharmaceutical compositioncomprising one or more glucose reabsorption inhibitors, one or more RXRmodulators, and a pharmaceutically acceptable carrier. In one aspect ofthe invention, the RXR modulator is an RXR agonist that increasesinsulin sensitivity in the subject. In another aspect of the invention,the RXR modulator is an RXR antagonist that increases insulinsensitivity in the subject.

[0377] In particular, the glucose reabsorption inhibitor is a SGLT1and/or SGLT2 inhibitor. More particularly, the glucose reabsorptioninhibitor is selected from a propiophenone, a dihydrochalcone, and aderivative thereof.

[0378] Specifically, the glucose reabsorption inhibitor is a compound ofFormula V:

[0379] wherein

[0380] Ar is aryl or heteroaryl;

[0381] OX is an optionally protected hydroxy group;

[0382] Y is hydrogen or alkyl; and

[0383] Z is glucopyranosyl wherein one or more hydroxy groups thereofmay optionally be substituted with one or more groups selected fromα-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted alkyl.

[0384] Preferably, Z is β-D-glucopyranosyl.

[0385] A preferred group of compounds of Formula V are compounds ofFormula I wherein substituents are as described in U.S. Pat. No.6,048,842, particularly claims 2 through 10.

[0386] A preferred group of compounds of Formula V are compounds ofFormula II wherein substituents are as described in U.S. Pat. No.5,830,873, particularly claims 2 through 8 and 13 through 16.

[0387] A preferred group of compounds of Formula V are compounds ofFormula IlIl wherein substituents are as described in U.S. Pat. No.5,767,094, particularly claims 2, 3, 8, and 9.

[0388] A preferred group of compounds of Formula V are compounds ofFormula IV wherein substituents are as described in U.S. Patent NO. U.S.Pat. Nos. 5,731,292 and 5,424,406, particularly claims 4 through 13 ofU.S. Pat. No. 5,731,292 and claims 6 through 13 and 15 through 18 ofU.S. Pat. No. 5,424,406.

[0389] Preferably, the glucose reabsorption inhibitor is selected fromT-1095 and T-1095A:

[0390] T-1095A is a selective and potent inhibitor of SGLT in thekidney. T-1095 is a pro-drug and converted to its active form T-1095A inthe liver. Oral administration of T-1095 has been shown to suppresselevated blood glucose levels by enhancing the excretion of glucose inrodent models of IDDM and NIDDM. Treatment for 3 weeks to 6 months withT-1095 reduced both fed and fasting blood glucose levels and HbA1c indiabetic rodent models (streptozotocin (STZ)-induced diabetic rat,yellow KK mice, db/db mice, Zucker Diabetic Fatty rats and GK rats). Inaddition, there was a decrease in the hyperinsulinemia,hypertriglyceridemia, and the development of microalbuminuria in theyellow KK mice and other diabetic mice models. The results of oralglucose tolerance test and hyperinsulinemic euglycemic clamp studiesrevealed the improvement of glucose tolerance and the reduction ofinsulin resistance. There was no observed sign of adding weight,infection in the urinary tracts, electrolyte imbalance in plasma,changes in food intake, acute hypoglycemic shock nor pathologicalchanges in the kidney during treatment with T-1095. The presence of thecarbonate may impart SGLT selectivity. For the intestinal SGLT-1,T-1095A is a better substrate than T-1095. The prodrug is hydrolysed invivo to yield T-1095A, which is also a better substrate for theinhibition of SGLT-2 in the kidney.

[0391] T-1095 or T-1095A may be protected with one or more hydroxyl ordiol protecting groups, examples of which are listed above in Section A.

[0392] For use in medicine, the salt or salts of the compounds ofFormula I, II, III, IV, or V refer to non-toxic “pharmaceuticallyacceptable salt or salts.” Other salts may, however, be useful in thepreparation of compounds according to this invention or of theirpharmaceutically acceptable salts. Representative organic or inorganicacids include, but are not limited to, hydrochloric, hydrobromic,hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic,glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric,benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic,benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic,p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic ortrifluoroacetic acid. Representative basic/cationic salts include, butare not limited to, benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium, or zinc. The compounds of Formula I, II,III, IV, or V, or a pharmaceutically acceptable salt thereof, mayinclude an intramolecular salt thereof, or a solvate or hydrate thereof.

[0393] F. Administration, Formulation, and Dosages

[0394] The utility of the disclosed compounds, compositions, andcombinations to treat disorders in glucose and lipid metabolism can bedetermined according to the procedures well known in the art (see thereferences listed below), as well as all the procedures described inU.S. Pat. Nos. 5,424,406, 5,731,292, 5,767,094, 5,830,873, and6,048,842, which are incorporated herein by reference. The compound maybe administered to a patient by any conventional route ofadministration, including, but not limited to, intravenous, oral,subcutaneous, intramuscular, intradermal and parenteral administration.Preferably, formulations are for oral administration.

[0395] The present invention also provides pharmaceutical compositionscomprising one or more glucose reabsorption inhibitors and one or moreRXR modulators in association with a pharmaceutically acceptablecarrier.

[0396] The daily dosage of the products may be varied over a wide rangefrom 1 to 1000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0,15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 2 times per day. The dosages,however, may be varied depending upon the requirement of the patients,the severity of the condition being treated and the compound beingemployed. The use of either daily administration or post-periodic dosingmay be employed. Preferably these compositions are in unit dosage formssuch as tablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, auto-injector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient oringredients are mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of one ormore glucose reabsorption inhibitors and one or more RXR modulators, ora pharmaceutically acceptable salt thereof. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient or ingredients are dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient or ingredients of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of material can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

[0397] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also include thesynthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

[0398] Advantageously, the combinations of one or more glucosereabsorption inhibitors and one or more RXR modulators of the presentinvention may be administered in. a single daily dose, or the totaldaily dosage may be administered in divided doses of two, three or fourtimes daily. Furthermore, one or more glucose reabsorption inhibitorsand/or one or more RXR modulators according to the present invention canbe administered in intranasal form via topical use of suitableintranasal vehicles, or via transdermal skin patches well known to thoseof ordinary skill in that art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

[0399] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

[0400] Wherein the present invention is directed to the administrationof a combination, the compounds may be co-administered simultaneously,sequentially, or in a single pharmaceutical composition. Where thecompounds are administered separately, the number of dosages of eachcompound given per day, may not necessarily be the same, e.g. where onecompound may have a greater duration of activity, and will therefore, beadministered less frequently.

[0401] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the strength of the preparation, the mode of administration, andthe advancement of theedisease condition. In addition, factors.associated with the particular patient being treated, including patientage, weight, diet and time of administration, will result in the need toadjust dosages.

[0402] The novel compositions of the present invention can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of lipids, includingbut not limited to amphipathic lipids such as phosphatidylcholines,sphingomyelins, phosphatidylethanolamines, phophatidylcholines,cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidicacids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyldimethylammonium propanes, and stearylamine, neutral lipids such astriglycerides, and combinations thereof. They may either containcholesterol or may be cholesterol-free.

[0403] From Formulae V, VI and other disclosed formulae it is evidentthat some compounds in the compositions of the invention may have one ormore asymmetric carbon atoms in their structure. It is intended that thepresent invention include within its scope the stereochemically pureisomeric forms of the compounds as well as their racemates.Stereochemically pure isomeric forms may be obtained by the applicationof art known principles. Diastereoisomers may be separated by physicalseparation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diastereomeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereospecificreactions.

[0404] Some compounds in the compositions of the present invention mayhave various individual isomers, such as trans and cis, and variousalpha and beta attachments (below and above the plane of the drawing).In addition, where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared as a single stereoisomeror in racemic form as a mixture of some possible stereoisomers. Thenon-racemic forms may be obtained by either synthesis or resolution. Thecompounds may, for example, be resolved into their componentsenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation. The compounds may also beresolved by covalent linkage to a chiral auxiliary, followed bychromatographic separation and/or crystallographic separation, andremoval of the chiral auxiliary. Alternatively, the compounds may beresolved using chiral chromatography. Unless otherwise noted, the scopeof the present invention is intended to cover all such isomers orstereoisomers per se, as well as mixtures of cis and trans isomers,mixtures of diastereomers and racemic mixtures of enantiomers (opticalisomers) as well.

[0405] The therapeutic effect of the glucose reabsorption inhibitoradministered in combination with an RXR modulator in treating diabetes,Syndrome X, or associated symptoms or complications can be shown bymethods known in the art. The following examples of combinationtreatment with SGLT inhibitors and RXR agonists are intended toillustrate the invention but not to limit it.

EXAMPLE 1 Effects on Plasma Glucose, Plasma Insulin, PlasmaTriglycerides, Plasma Free Fatty Acids, Liver Weight, and Body Weight

[0406] To examine the effect of T-1095 in combination with an RXRagonist, female db/db mice (6-7 weeks of age/Jackson Labs, ME) aretreated daily for 11 days with vehicle (0.5% methylcellulose), an RXRagonist such as MX-6054 (0.1 -10 mpk (mg/kg)), T-1095 (100 mpk), orMX-6054 plus T-1095. Mice (n=8 animals/group) receive the test compoundsor vehicle by oral gavage in a volume of 10 ml/kg of body weight. Bodyweight is recorded on day 1, prior to dosing, and. days 4, 8 and 11.Eighteen hours after the final dose, mice are weighed and anesthetizedwith CO₂/O₂ (70:30). Mice are then bled by retro-orbital sinus punctureinto 2 mL heparinized polypropylene tubes on ice. Plasma samples arethen assayed for glucose, insulin, triglycerides, and free fatty acids.Livers are excised, weighed and frozen.

[0407] The SGLT inhibitors and RXR agonists have distinct mechanisms ofaction. Improved glycemic control, measured as a decrease in plasmaglucose, plasma insulin, plasma free fatty acids, or plasmatriglycerides, or a combination thereof, can be observed at lowerconcentrations of an RXR agonist such as MX-6054 when given incombination with T-1095. Therefore, a leftward shift in thedose-response curve for effect of an RXR agonist such as MX-6054 on theabove parameters can become apparent. In addition, the weight gainobserved following treatment with RXR agonists is less pronounced whengiven with the SGLT inhibitor, since SGLT inhibitors' promotion of theurinary excretion of glucose and loss of calories from the body isdemonstrated by reduction in weight or weight gain. Also, since SGLTinhibitors promote a mild diuresis, the edema (and the edematous weightgain) commonly observed after treatment with RXR agonists can be lesspronounced or absent. A reduction in the amount of an RXR agonist suchas MX-6054 necessary to achieve efficacy in turn improves theside-effect profile. The decreased side effects can include suchconditions as fatty liver, increased liver weight, body weight gain,heart weight gain, edema, cardiac hypertrophy, hepatohypertrophy,hypoglycemia, and hepatotoxicity, or any combination thereof.

EXAMPLE 2 Effects on Plasma Glucose, Plasma Insulin, Plasma Free FattyAcids, Plasma Triglycerides, Liver Weight, and Body Weight

[0408] To examine the effect of T-1095 in combination with an RXRagonist, female db/db mice (6-7 weeks of age/Jackson Labs, ME) aretreated daily for 11 days with vehicle (0.5% methylcellulose), an RXRagonist such as MX-6054 (10 mpk), T-1095 (3, 10, 30, or 100 mpk), orMX-6054 plus T-1095. Mice (n=8 animals/group) receive the test compoundsor vehicle by oral gavage in a volume of 10 ml/kg of body weight. Bodyweight is recorded on day 1, prior to dosing, and days 4, 8 and 11.Eighteen hours after the final dose, mice are weighed and anesthetizedwith CO₂/O₂ (70:30). Mice are then bled by retro-orbital sinus punctureinto 2 mL heparinized polypropylene tubes on ice. Plasma samples arethen assayed for glucose, insulin, free fatty acids, and triglycerides.Livers are excised, weighed and frozen.

[0409] The SGLT inhibitors and RXR agonists have distinct mechanisms ofaction. The weight gain observed following treatment with RXR agonistsis less pronounced when given with the SGLT inhibitor, since SGLTinhibitors' promotion of the urinary excretion of glucose and loss ofcalories from the body is demonstrated by reduction in weight or weightgain. Also, since SGLT inhibitors promote a mild diuresis, the edema(and the edematous weight gain) commonly observed after treatment withRXR agonists can be less pronounced or absent. A reduction in the amountof RXR agonists necessary to achieve efficacy in turn improves theside-effect profile. The decreased side effects can include suchconditions as fatty liver, increased liver weight, body weight gain,increased heart weight/size, edema, cardiac hypertrophy,hepatohypertrophy, hypoglycemia, and hepatotoxicity, or any combinationthereof.

EXAMPLE 3 Effects on plasma Glucose, HbA1c, Hematocrit, Plasma Insulin,Plasma Triglycerides, Plasma Free Fatty Acids, Total Cholesterol, HDL,Plasma Drug Levels, Liver Weight, Heart Weight, Fat Content and BodyWeight

[0410] To examine the effect of T-1095 in combination with an RXRagonist, male ZDF rats (6 weeks of age/GMI) are treated daily for 28days with vehicle (0.5% methylcellulose), an RXR agonist such as MX-6054(0.1 mpk-10 mpk), T-1095 (3-100 mpk), or MX-6054 plus T-1095. Rats (n=8animals/group) receive the test compounds or vehicle by oral gavage in avolume of 2 ml/kg of body weight. Body weight is recorded on day 1,prior to dosing, and twice a week for the duration of the study. On theday prior to the final dose, animals are fasted overnight. One hourafter the final dose, rats are weighed and anesthetized with CO₂/O₂(70:30). Rats are then bled by retro-orbital sinus puncture into 2 mLheparinized polypropylene tubes on ice. Rats then receive a glucosechallenge (2 g/kg p.o) and are placed in metabolism cages for the urinecollection (4 hours). Animals are then sacrificed and epididymal fatpads, livers, and hearts are excised, weighed and frozen forhistological examination. Plasma samples are then assayed for glucose,HbA1c, insulin, hematocrit, plasma drug levels, total cholesterol, HDL,free fatty acids, and triglycerides. Urine volume and urinary glucose,protein, osmolarity, electrolytes (Na, K, Cl), BUN, creatinine aremeasured.

[0411] The SGLT inhibitors and RXR agonists have distinct mechanisms ofaction. Improved glycemic control, measured as a decrease in plasmaglucose, HbA1c, plasma insulin, or plasma triglycerides, or acombination thereof, can be observed at lower concentrations of RXRagonists when given in combination with T-1095. Therefore, a leftwardshift in the dose-response curve for effect of RXR agonists on the aboveparameters can become apparent. In addition, the weight gain observedfollowing treatment with RXR agonists is less pronounced when given withthe SGLT inhibitor, since SGLT inhibitors' promotion of the urinaryexcretion of glucose and loss of calories from the body is demonstratedby reduction in weight or weight gain. Also, since SGLT inhibitorspromote a mild diuresis, the edema (and the edematous weight gain)commonly observed after treatment with RXR agonists can be lesspronounced or absent. This can be demonstrated by a reduction in the RXRagonist-induced increase in heart weight. A reduction in the amount ofRXR agonists necessary to achieve efficacy in turn improves theside-effect profile. The decreased side effects can include suchconditions as fatty liver, increased liver weight, body weight gain,heart weight gain, edema, cardiac hypertrophy, hepatohypertrophy,hypoglycemia, and hepatotoxicity, or any combination thereof.

EXAMPLE 4 Effects on Plasma Glucose, HbA1c, Hematocrit, Plasma Insulin,Free Fatty Acids, Plasma Triglycerides, Plasma Drug Levels, LiverWeight, Heart Weight, and Body Weight

[0412] To examine the effect of T-1095 in combination with an RXRagonist, female db/db mice (6 weeks of age/Jackson Labs, ME) are treateddaily for 28 days with vehicle (0.5% methylcellulose), an RXR agonistsuch as MX-6054 (0.1 mpk-10 mpk), T-1095 (3-100 mpk), or MX-6054 plusT-1095. Mice (n=8 animals/group) receive the test compounds or vehicleby oral gavage in a volume of 10 ml/kg of body weight. Body weight isrecorded on day 1, prior to dosing, and twice a week for the duration ofthe study. One hour after the final dose, mice are weighed andanesthetized with CO₂/O₂ (70:30). Mice are then bled by retro-orbitalsinus puncture into 2 mL heparinized polypropylene tubes on ice. Micethen are then fasted overnight and bled by tail-clip prior to receivinga glucose challenge (2 g/kg p.o). Blood is collected at 30, 60, 120, and180 minutes after the challenge. Animals are then sacrificed and liversand hearts are excised, weighed and frozen for histological examination.Plasma samples are then assayed for glucose, HbA1c, insulin, hematocrit,drug levels, free fatty acids, and triglycerides.

[0413] The SGLT inhibitors and RXR agonists have distinct mechanisms ofaction. Improved glycemic control, measured as a decrease in plasmaglucose, HbA1c, plasma insulin, or plasma triglycerides, or acombination thereof, can be observed at lower concentrations of RXRagonists when given in combination with T-1095. Therefore, a leftwardshift in the dose-response curve for effect of RXR agonists on the aboveparameters can become apparent. In addition, the weight gain observedfollowing treatment with RXR agonists is less pronounced when given withthe SGLT inhibitor, since SGLT inhibitors' promotion of the urinaryexcretion of glucose and loss of calories from the body is demonstratedby reduction in weight or weight gain. Also, since SGLT inhibitorspromote a mild diuresis, the edema (and the edematous weight gain)commonly observed after treatment with RXR agonists can be lesspronounced or absent. This can be demonstrated by a reduction in the RXRagonist-induced increase in heart weight. A reduction in the amount ofRXR agonists necessary to achieve efficacy in turn improves theside-effect profile. The decreased side effects can include suchconditions as fatty liver, increased liver weight, body weight gain,heart weight gain, edema, cardiac hypertrophy, hepatohypertrophy,hypoglycemia, and hepatotoxicity, or any combination thereof.

EXAMPLE 5 Effects on Plasma Glucose, Plasma Triglycerides, Liver Weight,Heart Weight and Body Weight

[0414] To examine the effect of T-1095 in combination with a RXRagonist, male db/db mice (7 weeks of age/Jackson Labs, ME) were treateddaily for 11 days with vehicle (0.5% methylcellulose), an RXR agonistsuch as MX-6054 (0.1 mg/kg -10 mg/kg), T-1095 (100 mg/kg), or MX-6054plus T-1095. Mice (n=8 animals/group) received the test compounds orvehicle by oral gavage in a volume of 10 ml/kg of body weight. Bodyweight was recorded on day 1, prior to dosing, and days 4, 8 and 11. Twohours after the final dose (day 11), mice were weighed and anesthetizedwith CO₂/O₂ (70:30). Mice were then bled by retro-orbital sinus punctureinto 2 mL heparinized polypropylene tubes on ice. Livers were excised,weighed and frozen.

[0415] Plasma samples were then assayed for glucose and triglyceridesusing Trinder reagent (Sigma Diagnostics) and GPO-Trinder (SigmaDiagnostics). Results are shown in Tables 2 and 3. TABLE 2 Effect of 11day oral dosing of MX-6054 +/− T-1095 (100 mg/kg) in 7-8 week old femaledb/db mice. Effects on fed plasma glucose and triglyceride levels.Glucose Triglycerides (mg/dL) ± (mg/dL) ± Treatment SEM SEM VehicleControl 368 ± 68 248 ± 35 0.1 mpk MX-6054 357 ± 46 260 ± 24 0.3 mpkMX-6054 342 ± 41 262 ± 25 1 mpk MX-6054 406 ± 57 259 ± 28 3 mpk MX-6054255 ± 42 206 ± 24 10 mpk MX-6054 224 ± 13 * 189 ± 11 0.1 mpk MX-6054 +100 mpk T-1095 193 ± 12 ** 240 ± 24 0.3 mpk MX-6054 + 100 mpk T-1095 228± 12 * 220 ± 38 1 mpk MX-6054 + 100 mpk T-1095 226 ± 21 * 206 ± 29 3 mpkMX-6054 + 100 mpk T-1095 228 ± 18 213 ± 13 10 mpk MX-6054 + 100 mpkT-1095 185 ± 16 ** 141 ± 8 * 100 mpk T-1095 201 ± 9 * 196 ± 11

[0416] Livers and hearts were excised, weighed and frozen. Results areshown in Table 3. TABLE 3 Effect of 35 day oral dosing of MX-6054 +/−T-1095 in 6-7 wks old female db/db mice. Effects on body and liverweights. Vehicle Control −0.7 ± 1.3 1.91 ± 0.1 0.1 mpk MX-6054 −0.7 ±0.7 1.76 ± 0.11 0.3 mpk MX-6054   0.2 ± 0.4 1.93 ± 0.09 1 mpk MX-6054  0.6 ± 0.6 1.98 ± 0.09 3 mpk MX-6054 −0.8 ± 1.3 1.89 ± 0.09 10 mpkMX-6054   2.5 ± 1.1 2.38 ± 0.16 * 0.1 mpk MX-6054 + 100 mpk T-1095 −0.8± 1.3 1.71 ± 0.05 0.3 mpk MX-6054 + 100 mpk T-1095 −1.6 ± 0.4 1.67 ±0.05 1 mpk MX-6054 + 100 mpk T-1095 −1.0 ± 0.9 1.74 ± 0.13 3 mpkMX-6054 + 100 mpk T-1095 −0.3 ± 0.9 1.89 ± 0.11 10 mpk MX-6054 + 100 mpkT-1095 −2.4 ± 0.7 # 1.99 ± 0.08 # 100 mpk T-1095 0.7 ± 0.3 1.64 ± 0.07

[0417] The SGLT inhibitors and RXR agonists have distinct mechanisms ofaction. Improved glycemic control, measured as a decrease in plasmaglucose can be observed at lower concentrations of the RXR agonists whengiven in combination with T-1095. Specifically, a leftward shift in thedose-response curve for effect of RXR agonists on the plasma glucose wasobserved.

[0418] The above studies show that the oral administration of T-1095 incombination with an RXR modulator improved the status of markers ofdiabetes mellitus, including blood glucose, and triglyceride levels.

[0419] In addition, the weight gain observed following treatment withthe highest concentration of the RXR agonists was less pronounced whengiven with the SGLT inhibitor. This is most likely due to the ability ofthe SGLT inhibitors to promote the urinary excretion of glucose and lossof calories from the body. Treatment with MX-6054 also produced asignificant increase in liver weight which was prevented by theco-administration of T-1095. Therefore, unexpected improvement can beseen in adverse side effects such as increased body weight gain,increased liver weight, fafty liver hepatohypertrophy, hepatotoxicity,and hypoglycemia or any combination thereof.

[0420] The above examples can also show that the oral administration ofT-1095 in combination with an RXR modulator improve the status of othermarkers of diabetes mellitus including glycosylated hemoglobin (Hgb A1C)levels. Particularly, the oral administration of T-1095 in combinationwith one or more RXR modulators can reduce body weight or body weightgain as well as liver weight or liver weight gain, compared toadministration of one or more RXR modulators alone.

[0421] Thus, for treating diabetes, particularly Type II diabetesmellitus, or Syndrome X, a compound of Formulae I, II, III, IV, or V incombination with one or more RXR modulators, preferably RXR agoniststhat increases insulin sensitivity, may be employed comprisingadministering repeated oral doses of the compound of formula I in therange of about 25 to 1000 mg once or twice daily and repeated doses ofthe anti-diabetic agent or agents at jointly effective dosages. Thejointly effective dosage for RXR modulators disclosed herein may bereadily determined by those skilled in the art based on standard dosageguidelines. In particular, such combined administration can be effectiveto accomplish reduction of body weight, body weight gain, liver weight,or liver weight gain in the subject.

[0422] Additionally, a method comprising (a) administering to a subjecta jointly effective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of an RXRmodulator can be used to reduce body weight, body weight gain, or liverweight of the subject in need thereof, wherein the combinedadministration can be in any order and the combined jointly effectiveamounts provide the desired therapeutic effect.

[0423] Also, a method comprising (a) administering to a subject ajointly effective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of an RXRmodulator can be used to control body weight, body weight gain, liverweight, or liver weight gain of the subject having diabetes, Syndrome X,or associated symptoms or complications, wherein the combinedadministration can be in any order and the combined jointly effectiveamounts providing the desired therapeutic effect.

[0424] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation andthe advancement of the disease condition. In addition, factorsassociated with the particular patient being treated, includingpatient's sex, age, weight, diet, time of administration and concomitantdiseases, will result in the need to adjust dosages.

[0425] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the usual variations, adaptations and/ormodifications as come within the scope of the following claims and theirequivalents.

What is claimed is:
 1. A method for treating diabetes or Syndrome X, orassociated symptoms or complications thereof in a subject, comprising(a) administering to said subject a jointly effective amount of aglucose reabsorption inhibitor; and (b) administering to said subject ajointly effective amount of an RXR modulator, said co-administrationbeing in any order and the combined jointly effective amounts providingthe desired therapeutic effect.
 2. The method of claim 1, wherein theRXR modulator is an RXR agonist.
 3. The method of claim 1, wherein theRXR modulator is selected from (a) bexarotene; (b) 9-cis-retinoic acid;(c) AGN-4326; (d) LGD 1324; (e) LG 100754; (f) LY-510929; (g) LGD 1268;and (h) LG
 100264. 4. The method of claim 1, wherein the RXR modulatoris a compound of Formula (VI),

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein n and m are independently 0 or 1; R₁ and R₂ are 1)independently or together hydrogen, alkyl, substituted alkyl, haloalkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkoxy, hydroxyl, acyl, amino, mono-substituted amino,di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide or haloalkoxy; or 2) R₁ and R₂ together with thearomatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl residue that may optionallycomprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl; R₃ and R₄are independently or together hydrogen, alkyl, substituted alkyl,haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino,di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea,arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substitutedalkoxy, haloalkoxy, thioalkyl, thiohaloalkoxy; carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide; A is —CR₆R₇— wherein R₆ and R₇ areindependently or together hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, haloalkoxy; or R₆ and R₇ together form a cycloalkylresidue that may optionally comprise 1 or 2 heteroatoms selected from O,S, NH or N-alkyl; Ar is Formula VII, VIII, IX or X:

wherein R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkoxy; carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide; R₅is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;

represents a bond present or absent; and W, X, Y and Z are independentlyor together —C(O)—, —C(S)—, —S—, —O—, or —NH— residues.
 5. The method ofclaim 4, wherein n is 1, R₁ and R₂ together with the aromatic ringbonded thereto form a substituted cycloalkyl optionally comprising 1 or2 heteroatoms selected from O, S, NH or N-alkyl, and R₃ is alkyl orsubstituted alkyl.
 6. The method of claim 4, wherein n is 1, A is—CR₆R₇— wherein R₆ and R₇ are independently or together alkyl, or R₆ andR₇ together form a cycloalkyl comprising 1 or 2 oxygen atoms and morepreferably a 1,3-dioxolane ring.
 7. The method of claim 4, wherein n is1, the group

is 2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione,isoxazolidinedione, 2,4-imidazolidinedione or2,4-thioxo-4-imidazolidinedione.
 8. The method of claim 4, wherein n is1, and the compound of Formula VI is selected from3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione;4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4-thiazolidinedione;4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4-thiazolidinedione;4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo-2,4-thiazolidinedione;4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo-2,4-thiazolidinedione;4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo-2,4-imidazolidinedione;4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo-2,4-imidazolidinedione;4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4-imidazolidinedione;4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4-imidazolidinedione;4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4-thiazolidinedione;4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4-thiazolidinedione;4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-2,4-thiazolidinedione;4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo-2,4-thiazolidinedione;4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-2,4-imidazolidinedione;4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo-2,4-imidazolidinedione;4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4-imidazolidinedione;and4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4-imidazolidinedione.9. The method of claim 4, wherein the RXR modulator is MX-6054.
 10. Themethod of claim 1, wherein the diabetes or Syndrome X, or associatedsymptoms or complications thereof is selected from IDDM, NIDDM, IGT,IFG, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis,polycystic ovary syndrome, hypertension, ischemia, stroke, heartdisease, irritable bowel disorder, inflammation, and cataracts.
 11. Themethod of claims 1, 2, or 4, wherein the diabetes or Syndrome X, orassociated symptoms or complication thereof is IDDM.
 12. The method ofclaims 1, 2, or 4, wherein the diabetes or Syndrome X, or associatedsymptoms or complications thereof is NIDDM.
 13. The method of claims 1,2, or 4, wherein the diabetes or Syndrome X, or associated symptoms orcomplications thereof is IGT or IFG.
 14. The method of claims 1, 2, or4, further comprising administering to said subject a jointly effectiveamount of a third antidiabetic agent.
 15. The method of claim 14,wherein the third antidiabetic agent is selected from (aa) insulins,(bb) insulin analogues; (cc) insulin secretion modulators, and (dd)insulin secretagogues.
 16. The method of claim 15, wherein the diabetesor Syndrome X, or associated symptoms or complications thereof is IDDM.17. The method of claims 1, 2, 4, or 8, wherein the glucose reabsorptioninhibitor is an SGLT inhibitor.
 18. The method of claim 17, wherein theglucose reabsorption inhibitor is an SGLT1 inhibitor.
 19. The method ofclaim 17, wherein the glucose reabsorption inhibitor is an SGLT2inhibitor.
 20. The method of claim 17, wherein the glucose reabsorptioninhibitor is selected from a dihydrochalcone, a propiophenone, and aderivative thereof.
 21. The method of claim 20, wherein the glucosereabsorption inhibitor is a compound of Formula (V)

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein Ar is aryl or heteroaryl; OX is an optionallyprotected hydroxy group; Y is hydrogen or alkyl; and Z is glucopyranosylwherein one or more hydroxy groups thereof may optionally be substitutedwith one or more groups selected from α-D-glucopyranosyl, alkanoyl,alkoxycarbonyl, and substituted alkyl.
 22. The method of claim 21,wherein the glucose reabsorption inhibitor is a compound of Formula (IV)

wherein Ar is an aryl group, R¹ is hydrogen atom or an acyl group, R² ishydrogen atom, an acyl group or α-D-glucopyranosyl group, or R¹ and R²may combine together to form a substituted methylene group, R³ and R⁴are each hydrogen atom or an acyl group, and OR⁵ is a protected orunprotected hydroxy group or a lower alkoxy group.
 23. The method ofclaim 21, wherein the glucose reabsorption inhibitor is a compound ofFormula (III)

wherein R′ is a lower alkanoyl group, and R″ is a hydrogen atom, or R′is a hydrogen atom, and R″ is a lower alkoxycarbonyl group.
 24. Themethod of claim 21, wherein the glucose reabsorption inhibitor is acompound of Formula (II)

wherein X is an oxygen atom, a sulfur atom or a methylene group, OY is aprotected or unprotected hydroxy group, Z is a β-D-glucopyranosyl groupor 4-O-(α-D-glucopyranosyl)-β-D-glucopyranosyl group wherein one or morehydroxy groups of these groups may optionally be acylated, and thedotted line means the presence or absence of a double bond.
 25. Themethod of claim 21, wherein the glucose reabsorption inhibitor is acompound of Formula (I)

wherein OX is a hydroxy group which may optionally be protected, Y is alower alkyl group, and Z is a β-D-glucopyranosyl group wherein one ormore hydroxy groups may optionally be protected.
 26. The method of claim25, wherein the glucose reabsorption inhibitor is T-1095 or T-1095A

with one or more hydroxyl or diol protecting groups, or apharmaceutically acceptable salt thereof.
 27. The method of claim 25,wherein the glucose reabsorption inhibitor is T-1095 or T-1095A,

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof.
 28. The method of claim 25 wherein the glucosereabsorption inhibitor is T-1095 or T-1095A with one or more hydroxyl ordiol protecting groups, or an optical isomer, enantiomer, diastereomer,racemate or racemic mixture thereof, ester, prodrug form, or apharmaceutically acceptable salt thereof.
 29. The method of claim 28wherein the glucose reabsorption inhibitor is T-1095.
 30. The method ofclaim 28 wherein the glucose reabsorption inhibitor is T-1095A.
 31. Themethod of claimS 2, 3, 4, 8, or 9, wherein the glucose reabsorptioninhibitor is selected from the glucose reabsorption inhibitors describedin claim 25 or
 28. 32. The method of claim 28, wherein the jointlyeffective amount of T-1095 or T-1095A is from about 10 to 1000 mg. 33.The method of claim 28, wherein the jointly effective amount of T-1095or T-1095A is an amount sufficient to reduce the plasma glucoseexcursion following a meal.
 34. A method for inhibiting the onset ofdiabetes or Syndrome X, or associated symptoms or complications thereofin a subject, said method comprising (a) administering to said subject ajointly effective amount of a glucose reabsorption inhibitor; and (b)administering to said subject a jointly effective amount of an RXRmodulator, said co-administration being in any order and the combinedjointly effective amounts providing the desired prophylactic effect. 35.The method of claim 34, wherein said onset is from pre-diabetic state toNIDDM.
 36. A pharmaceutical composition comprising a glucosereabsorption inhibitor, a RXR modulator, and a pharmaceuticallyacceptable carrier.
 37. The pharmaceutical composition of claim 36,wherein the RXR modulator is an RXR agonist.
 38. The pharmaceuticalcomposition of claim 37, wherein the RXR modulator is selected from (a)bexarotene; (b) 9-cis-retinoic acid; (c) AGN-4326; (d) LGD 1324; (e) LG100754; (f) LY-510929; (g) LGD 1268; (h) LG 100264; and (i) MX-6054. 39.The pharmaceutical composition of claim 37, wherein the RXR modulator isselected from a compound of Formula (VI),

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein n and m are independently 0 or 1; R₁ and R₂ are 1)independently or together hydrogen, alkyl, substituted alkyl, haloalkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkoxy, hydroxyl, acyl, amino, mono-substituted amino,di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide or haloalkoxy; or 2) R₁ and R₂ together with thearomatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl residue that may optionallycomprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl; R₃ and R₄are independently or together hydrogen, alkyl, substituted alkyl,haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino,di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea,arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substitutedalkoxy, haloalkoxy, thioalkyl, thiohaloalkoxy; carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide; A is —CR₆R7— wherein R₆ and R₇ areindependently or together hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, haloalkoxy; or R₆ and R₇ together form a cycloalkylresidue that may optionally comprise 1 or 2 heteroatoms selected from O,S, NH or N-alkyl; Ar is Formula VII, VIII, IX or X:

wherein R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkoxy; carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide; R₅is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;

represents a bond present or absent; and W, X, Y and Z are independentlyor together —C(O)—, —C(S)—, —S—, —O—, or —NH— residues.
 40. Thepharmaceutical composition of claim 36, 37, 38, or 39, wherein theglucose reabsorption inhibitor is an SGLT inhibitor.
 41. Thepharmaceutical composition of claim 40, wherein the glucose reabsorptioninhibitor is an SGLT1 inhibitor.
 42. The pharmaceutical composition ofclaim 40, wherein the glucose reabsorption inhibitor is an SGLT2inhibitor.
 43. The pharmaceutical composition of claim 40, wherein theglucose reabsorption inhibitor is selected from a dihydrochalcone, apropiophenone, and a derivative thereof.
 44. The pharmaceuticalcomposition of claim 43, wherein the glucose reabsorption inhibitor is acompound of Formula (V)

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein Ar is aryl or heteroaryl; OX is an optionallyprotected hydroxy group; Y is hydrogen or alkyl; and Z is glucopyranosylwherein one or more hydroxy groups thereof may optionally be substitutedwith one or more groups selected from α-D-glucopyranosyl, alkanoyl,alkoxycarbonyl, and substituted alkyl.
 45. The pharmaceuticalcomposition of claim 44, wherein the glucose reabsorption inhibitor is acompound of Formula (I)

wherein OX is a hydroxy group which may optionally be protected, Y is alower alkyl group, and Z is a β-D-glucopyranosyl group wherein one ormore hydroxy groups may optionally be protected.
 46. The pharmaceuticalcomposition of claim 45, wherein the glucose reabsorption inhibitor isT-1095 or T-1095A, optionally having one or more hydroxyl or diolprotecting groups, or an optical isomer, enantiomer, diastereomer,racemate or racemic mixture thereof, ester, prodrug form, or apharmaceutically acceptable salt thereof.
 47. A process for formulatinga pharmaceutical composition, comprising formulating together a glucosereabsorption inhibitor, an RXR modulator, and a pharmaceuticallyacceptable carrier.
 48. The process of claim 47, wherein the RXRmodulator is an RXR agonist.
 49. The process of claim 47, wherein theRXR modulator is selected from (a) bexarotene; (b) 9-cis-retinoic acid;(c) AGN-4326; (d) LGD 1324; (e) LG 100754; (f) LY-510929; (g) LGD 1268;(h) LG 100264; and (i) MX-6054.
 50. The process of claim 47, wherein theRXR modulator is a compound of Formula (VI),

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein n and m are independently 0 or 1; R₁ and R₂ are 1)independently or together hydrogen, alkyl, substituted alkyl, haloalkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkoxy, hydroxyl, acyl, amino, mono-substituted amino,di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide or haloalkoxy; or 2) R₁ and R₂ together with thearomatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl residue that may optionallycomprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl; R₃ and R₄are independently or together hydrogen, alkyl, substituted alkyl,haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino,di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea,arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substitutedalkoxy, haloalkoxy, thioalkyl, thiohaloalkoxy; carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide; A is —CR₆R₇— wherein R₆ and R₇ areindependently or together hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, haloalkoxy; or R₆ and R₇ together form a cycloalkylresidue that may optionally comprise 1 or 2 heteroatoms selected from O,S, NH or N-alkyl; Ar is Formula VII, VIII, IX or X:

wherein R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkoxy; carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide; R₅is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;

represents a bond present or absent; and W, X, Y and Z are independentlyor together —C(O)—, —C(S)—, —S—, —O—, or —NH— residues.
 51. The processof claims 47, 48, 49, or 50, wherein the glucose reabsorption inhibitoris an SGLT inhibitor.
 52. The process of claim 51, wherein the glucosereabsorption inhibitor is an SGLT1 inhibitor.
 53. The process of claim51, wherein the glucose reabsorption inhibitor is an SGLT2 inhibitor.54. The process of claim 51, wherein the glucose reabsorption inhibitoris selected from a dihydrochalcone, a propiophenone, and a derivativethereof.
 55. The process of claim 54, wherein the glucose reabsorptioninhibitor is a compound of Formula (V)

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein Ar is aryl or heteroaryl; OX is an optionallyprotected hydroxy group; Y is hydrogen or alkyl; and Z is glucopyranosylwherein one or more hydroxy groups thereof may optionally be substitutedwith one or more groups selected from α-D-glucopyranosyl, alkanoyl,alkoxycarbonyl, and substituted alkyl.
 56. The process of claim 55,wherein the glucose reabsorption inhibitor is a compound of Formula (I)

wherein OX is a hydroxy group which may optionally be protected, Y is alower alkyl group, and Z is a β-D-glucopyranosyl group wherein one ormore hydroxy groups may optionally be protected.
 57. The process ofclaim 56, wherein the glucose reabsorption inhibitor is T-1095 orT-1095A, optionally having one or more hydroxyl or diol protectinggroups, or an optical isomer, enantiomer, diastereomer, racemate orracemic mixture thereof, ester, prodrug form, or a pharmaceuticallyacceptable salt thereof.
 58. A process for making a pharmaceuticalcomposition comprising mixing one or more glucose reabsorptioninhibitors in combination with an RXR modulator for the preparation of amedicament for treating a condition selected from IDDM, NIDDM, IGT, IFG,obesity, nephropathy, neuropathy, retinopathy, atherosclerosis,polycystic ovary syndrome, hypertension, ischemia, stroke, heartdisease, irritable bowel disorder, inflammation, and cataracts.
 59. Theprocess of claim 58, wherein the RXR modulator is an RXR agonist. 60.The process of claim 58, wherein the RXR modulator is selected from (a)bexarotene; (b) 9-cis-retinoic acid; (c) AGN-4326; (d) LGD 1324; (e) LG100754; (f) LY-510929; (g) LGD 1268; (h) LG 100264; and (i) MX-6054. 61.The process of claim 58, wherein the RXR modulator is a compound ofFormula (VI),

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein n and m are independently 0 or 1; R ₁ and R₂are 1) independently or together hydrogen, alkyl, substituted alkyl,haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,alkoxy, substituted alkoxy, hydroxyl, acyl, amino, mono-substitutedamino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide or haloalkoxy; or 2) R₁ and R₂ together with thearomatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl residue that may optionallycomprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl; R₃ and R₄are independently or together hydrogen, alkyl, substituted alkyl,haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino,di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea,arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substitutedalkoxy, haloalkoxy, thioalkyl, thiohaloalkoxy; carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide; A is —CR₆R₇— wherein R₆ and R₇ areindependently or together hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, haloalkoxy; or R₆ and R₇ together form a cycloalkylresidue that may optionally comprise 1 or 2 heteroatoms selected from O,S, NH or N-alkyl; Ar is Formula VII, VIII, IX or X:

wherein R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkoxy; carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide; R₅is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;

represents a bond present or absent; and W, X, Y and Z are independentlyor together —C(O)—, —C(S)—, —S—, —O—, or —NH— residues.
 62. The processof claims 58, 59, 60, or 61, wherein the glucose reabsorption inhibitoris an SGLT inhibitor.
 63. The process of claim 62, wherein the glucosereabsorption inhibitor is an SGLT1 inhibitor.
 64. The process of claim62, wherein the glucose reabsorption inhibitor is an SGLT2 inhibitor.65. The process of claim 62, wherein the glucose reabsorption inhibitoris selected from a dihydrochalcone, a propiophenone, and a derivativethereof.
 66. The process of claim 65, wherein the glucose reabsorptioninhibitor is a compound of Formula (V)

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein Ar is aryl or heteroaryl; OX is an optionallyprotected hydroxy group; Y is hydrogen or alkyl; and Z is glucopyranosylwherein one or more hydroxy groups thereof may optionally be substitutedwith one or more groups selected from α-D-glucopyranosyl, alkanoyl,alkoxycarbonyl, and substituted alkyl.
 67. The process of claim 66,wherein the glucose reabsorption inhibitor is a compound of Formula (I)

wherein OX is a hydroxy group which may optionally be protected, Y is alower alkyl group, and Z is a β-D-glucopyranosyl group wherein one ormore hydroxy groups may optionally be protected.
 68. The process ofclaim 67, wherein the glucose reabsorption inhibitor is T-1095 orT-1095A, optionally having one or more hydroxyl or diol protectinggroups, or an optical isomer, enantiomer, diastereomer, racemate orracemic mixture thereof, ester, prodrug form, or a pharmaceuticallyacceptable salt thereof.
 69. A method for inhibiting the progression ofa prediabetic condition in a subject to a diabetic condition, comprising(a) administering to said subject a jointly effective amount of aglucose reabsorption inhibitor; and (b) administering to said subject ajointly effective amount of an RXR modulator, said co-administrationbeing in any order and the combined jointly effective amounts providingthe desired inhibiting effect.
 70. The method of claim 69 wherein saidcondition is IGT or IFG.
 71. The method of claim 69 wherein saidinhibiting of the progression of a prediabetic condition is preventionof the progression of the prediabetic condition to a diabetic condition.72. The method of claim 71 wherein the RXR modulator is an RXR agonist.73. The method of claim 71 wherein the RXR modulator is selected from(a) bexarotene; (b) 9-cis-retinoic acid; (c) AGN-4326; (d) LGD 1324; (e)LG 100754; (f) LY-510929; (g) LGD 1268; (h) LG 100264; and (i) MX-6054.74. The method of claim 71 wherein the RXR modulator is a compound ofFormula (VI),

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein n and m are independently 0 or 1; R₁ and R₂ are 1)independently or together hydrogen, alkyl, substituted alkyl, haloalkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkoxy, hydroxyl, acyl, amino, mono-substituted amino,di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide or haloalkoxy; or 2) R₁ and R₂ together with thearomatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl residue that may optionallycomprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl; R₃ and R₄are independently or together hydrogen, alkyl, substituted alkyl,haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino,di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea,arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substitutedalkoxy, haloalkoxy, thioalkyl, thiohaloalkoxy; carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide; A is —CR₆R₇— wherein R₆ and R₇ areindependently or together hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, haloalkoxy; or R₆ and R₇ together form a cycloalkylresidue that may optionally comprise 1 or 2 heteroatoms selected from O,S, NH or N-alkyl; Ar is Formula VII, VIII, IX or X:

wherein R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkoxy; carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide; R₅is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;

represents a bond present or absent; and W, X, Y and Z are independentlyor together —C(O)—, —C(S)—, —S—, —O—, or —NH— residues.
 75. The methodof claims 69, 70, 71, 72, 73, or 74, wherein the glucose reabsorptioninhibitor is an SGLT inhibitor.
 76. The method of claim 75 wherein theglucose reabsorption inhibitor is selected from a dihydrochalcone, apropiophenone, and a derivative thereof.
 77. The method of claim 76,wherein the glucose reabsorption inhibitor is a compound of Formula (V)

or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture thereof, ester, prodrug form, or a pharmaceutically acceptablesalt thereof, wherein Ar is aryl or heteroaryl; OX is an optionallyprotected hydroxy group; Y is hydrogen or alkyl; and Z is glucopyranosylwherein one or more hydroxy groups thereof may optionally be substitutedwith one or more groups selected from α-D-glucopyranosyl, alkanoyl,alkoxycarbonyl, and substituted alkyl.
 78. The method of claim 77,wherein the glucose reabsorption inhibitor is a compound of Formula (I)

wherein OX is a hydroxy group which may optionally be protected, Y is alower alkyl group, and Z is a β-D-glucopyranosyl group wherein one ormore hydroxy groups may optionally be protected.
 79. The method of claim78, wherein the glucose reabsorption inhibitor is T-1095 or T-1095A,optionally having one or more hydroxyl or diol protecting groups, or anoptical isomer, enantiomer, diastereomer, racemate or racemic mixturethereof, ester, prodrug form, or a pharmaceutically acceptable saltthereof.